How do you manage GI side effects related to CFTR modulator therapy?

We have found that for most patients liver enzymes abnormalities are small and transient; however, for about 1% of patients there are severe elevations and these patients are much more difficult to manage, even after withdrawal, and tough to re-challenge; it is also not patients with severe liver disease before; indirect hyperbilirubinemia is quite common; for the other GI side effects you mentioned, we use all the above techniques until something works (and most patients want to stay on med, at least on some dose, even if reduced); interestingly for a couple of patients with severe side effects we have done a repeat sweat test on reduced dose and it is greatly reduced from baseline.

Described GI side effects of CFTR modulator therapy ranged from non-specific abdominal discomfort to abnormal liver function test with the incidence reported between 2-25%. Only a small percentage of patients with GI side effects required discontinuation of treatment with the incidence range between 0.2-4% in the real-world study (Dagenais et al., PMID 33374882). The common laboratory side effects of CFTR modulators are transaminitis and elevated serum bilirubin. The CFTR modulator is to be held when transaminases are >3x ULN or serum bilirubin >2x ULN, the levels are repeated every 6 weeks until there is a resolution of the levels. If the benefit is worth the re-challenge, the CFTR modulator will be resumed at an alternative dosing (i.e. f...